Patients with peripheral neuropathy suffer from debilitating sensory and motor symptoms. Developmental defects or damage to Schwann cells or axons can cause neuropathy. In the peripheral nervous system, Schwann cells wrap the axons in nerves and form the myelin sheath. Understanding the mechanisms that regulate Schwann cells is crucial to approaching therapies for remyelination and prevention of axonal damage in neuropathy patients. Studies in zebrafish, a powerful vertebrate model system with myelinated nerves, have led to key discoveries in nerve development, including the role of one Neuregulin isoform (type III) as a guidance cue for Schwann cells migrating in growing nerves. I hypothesize that changes in the localization or levels of Nrg1 type III on axons and ErbB receptors on Schwann cells drive different developmental decisions of Schwann cells, and that Nrg1 type I and type II signals cooperate with type III to control different steps of Schwann cell development. This project will discover the roles of the remaining vertebrate Nrg1 isoforms (type I and II) by using genome editing to generate isoform-specific Nrg1 mutants. Analyses of the phenotypes of these novel mutants will define the functions of type I and type II Nrg1 isoforms in vivo. The ability of Nrg1 type I and II to guide Schwann cells to ectopic locations will be tested n transgenic zebrafish. Nrg1 signaling functions throughout Schwann cell development to control specification, migration, proliferation and myelination, but it remains a major challenge to understand how Nrg1 controls so many different steps of Schwann cell development. One possibility is that Nrg1 level or distribution changes dynamically to define each stage of Schwann cell development. Creation of a tagged Nrg1 knock-in allele will allow changes in the localization and levels of endogenous Nrg1 to be monitored in vivo. Nrg1 signals though heterodimeric ErbB2/3 receptors on Schwann cells as they migrate towards the axon terminus, but it is not known whether ErbB receptors or downstream signaling molecules are polarized within migrating Schwann cells. Using antibodies and tagged receptors, the distribution and activity of ErbB receptors will be tested in migrating Schwann cells. To increase the levels of ErbB receptor activity, we will express constitutively active ErbB receptors and measure impact on migration, proliferation and myelination in vivo. These experiments will examine the mechanisms underlying regulation of Schwann cell development, myelination, and ultimately peripheral neuropathy. Despite the prevalence and severity of peripheral neuropathies, there is no cure for these diseases. This emphasizes the need to understand the mechanisms that control Schwann cell development and myelination, which may provide approaches toward therapeutic remyelination and prevention of axonal damage. This proposal will provide new animal models of neuropathy, elucidate the pathophysiology of neuropathy, and suggest roads toward new therapies.